Oncotarget

Research Papers:

NPM/ALK mutants resistant to ASP3026 display variable sensitivity to alternative ALK inhibitors but succumb to the novel compound PF-06463922

Luca Mologni _, Monica Ceccon, Alessandra Pirola, Giampaolo Chiriano, Rocco Piazza, Leonardo Scapozza and Carlo Gambacorti-Passerini

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Oncotarget. 2015; 6:5720-5734. https://doi.org/10.18632/oncotarget.3122

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Abstract

Luca Mologni1, Monica Ceccon1, Alessandra Pirola1, Gianpaolo Chiriano2, Rocco Piazza1, Leonardo Scapozza2, Carlo Gambacorti-Passerini1,3

1University of Milano-Bicocca, Dept. of Health Sciences, Monza, Italy

2University of Geneva, School of Pharmaceutical Sciences, Geneva, Switzerland

3San Gerardo Hospital, Hematology Unit, Monza, Italy

Correspondence to:

Luca Mologni, e-mail: luca.mologni@unimib.it

Keywords: NPM/ALK, inhibitor, resistance, ASP3026, PF-06463922

Received: September 19, 2014     Accepted: January 09, 2015     Published: January 30, 2015

ABSTRACT

ALK is involved in the onset of several tumors. Crizotinib (XalkoriTM), a potent ALK inhibitor, represents the current front-line treatment for ALK+ NSCLC and shows great clinical efficacy. However, resistant disease often develops after initial response. ASP3026 is a novel second-generation ALK inhibitor with activity on crizotinib-resistant ALK-L1196M gatekeeper mutant. As resistance is likely to be a relevant hurdle for any drug, we sought to determine the resistance profile of ASP3026 in the context of NPM/ALK+ ALCL. We selected six ASP3026-resistant cell lines by culturing human ALCL cells in the presence of increasing concentrations of drug. The established resistant cell lines carry several point mutations in the ALK kinase domain (G1128S, C1156F, I1171N/T, F1174I, N1178H, E1210K and C1156F/D1203N were the most frequent) that are shown to confer resistance to ASP3026 in the Ba/F3 cell model. All mutants were profiled for cross-resistance against a panel of clinically relevant inhibitors including ceritinib, alectinib, crizotinib, AP26113 and PF-06463922. Finally, a genetically heterogeneous ASP3026-resistant cell line was exposed to second-line treatment simulations with all inhibitors. The population evolved according to relative sensitivity of its mutant subclones to the various drugs. Compound PF-06463922 did not allow the outgrowth of any resistant clone, at non-toxic doses.


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